In general, transferases catalyze the transfer of one molecular group from a donor molecule to an acceptor molecule. Examples of such molecular groups include phosphate, amino, methyl, acetyl, acyl, phosphatidyl, phosphoribosyl, among other groups. The methyltransferase family is a large superfamily of enzymes that regulate biological processes by catalyzing the transfer of methyl groups to a wide variety of endogenous and exogenous compounds, including DNA, RNA, proteins, hormones, neurotransmitters, drugs, and xenobiotics (Weinshilboum et al. (1999) Annu. Rev. Pharmacol. Toxicol. 39:19-52).
Methylation of DNA can play an important role in the control of gene expression in mammalian cells. DNA methyltransferases are involved in DNA methylation and catalyze the transfer of a methyl group from S-adenosylmethionine to cytosine residues to form 5-methylcytosine, a modified base that is found mostly at CpG sites in the genome. The presence of methylated CpG islands in the promoter region of genes can suppress their expression. This process may be due to the presence of 5-methylcytosine, which apparently interferes with the binding of transcription factors or other DNA-binding proteins to block transcription. In different types of tumors, aberrant or accidental methylation of CpG islands in the promoter region has been observed for many cancer-related genes, resulting in the silencing of their expression. Such genes include tumor suppressor genes, genes that suppress metastasis and angiogenesis, and genes that repair DNA (Momparler and Bovenzi (2000) J. Cell Physiol. 183:145-54).
Methylation of proteins is a post-translational modification which can regulate the activity and subcellular localization of numerous proteins. Methylation of proteins can play an important role in protein repair and reversal of protein aging. Proteins undergo a variety of spontaneous degradation processes, including oxidation, glycation, deamidation, isomerization, and racemization. These non-enzymatic modifications can produce functionally damaged species that reflect the action of aging at the molecular level (Stadtman (1992) Science 257:1220-1224; Martin et al. (1996) Nat. Genet. 13:25-34). Methylation of these damaged proteins e.g., by protein L-isoaspartyl methyltransferase (Shimizu et al. (2000) Arch. Biochem. Biophys. 381:225-34) can play a part in the repair pathway. Protein methylation is also known to be important in cellular stress responses (Desrosiers and Tanguay (1988) J. Biol. Chem. 263:4686-4692). Moreover, protein methyltransferases have recently been demonstrated to be important in cellular signaling events, for example, in receptor-mediated and/or differentiation-dependent signaling (Lin et al. (1996) J. Biol. Chem. 271:15034-15044; Abramovich et al. (1997) EMBO J. 16:260-266).
Methylation is a process important for the catabolism of small molecules, such as thiol compounds and neurotransmitters. A deficiency in thiol compound detoxification by methylation is being investigated for its role in rheumatoid arthritis (Waring and Emery (1993) Baillieres Clin. Rheumatol. 6:337-50). Inhibition of dopamine methylation and inactivation by catechol-O-methyl transferase is a goal for therapy of Parkinson's disease (Goldstein and Lieberman (1992) Neurology 42(suppl):8-12).